Process for the production of alpha-methyl-alpha-phenyl-beta-ethylsuccinimide



United States Patent M 3,183,245 PROCESS FOR Tl-m PRQDUCTIQN (PFUL-METHYL- a-PI ENYL-fl-ETHYLdUCCHNIMlDE Charles A. Miller, Detroit, andRobert L. Hull, Madison Heights, Mich, assignors to Parke, Davis 8;Company, Detroit, Mich, a corporation of Michigan No Drawing. Filed Ian.4, 1963, Ser. No. 249,334 2 Claims. ((ll. 260-4265) This is acontinuation-in-part of copending application Serial No. 178,565, filedMarch 9, 1962, now issued as US. Patent 3,162,648.

This invention relates to succinimide compounds. More particularly theinvention relates to a-rnethyl-u-phenyl- B-ethylsuccinimide compounds ofthe formula to methods for their production and to their pharmaceuticalapplications; where R represents hydrogen or methyl.

In accordance with the invention, compounds of the foregoing formula canbe produced by heating a-methyla-phenyl-/3-ethylsuccinic acid or areactive derivative thereof with a compound of the formula where R is asdefined before. Some examples of suitable reactive derivatives oftic-methyl-u-phenyl-fi-ethylsuccinic acid are the anhydride and the acidhalides. The reaction of a-methyl-u-phenyl-B-ethylsuccinic acid and itsreactive derivatives with ammonia or methylamine can follow a stepwisecourse in which an intermediate reaction product is formed and thenundergoes further reaction to give the desireda-rnethyl-a-phenyl-fl-ethylsuccinimide compound upon heating attemperatures substantially in excess of room temperature. Whena-methyl-a-phenyhfl-ethylsuccinic acid is employed as a startingmaterial, the intermediate reaction product is a salt of the acid andammonia or methylarnine. Upon heating this salt, preferably at aboutl50250 C., it undergoes dehydration and ring closure to yield thedesired succinimide. When OL-Il'lCthYia-phenyl-,8-ethylsuccinicanhydride is used as a starting material, the intermediate reactionproduct is a half amide, that is, a substituted succinamic acid or asalt thereof. Upon heating, preferably in the presence of a dehydratingagent such as acetyl chloride or acetic anhydride, the half amideundergoes dehydration and ring closure to yield the desired succinimide.When u-methyl-a-phenylfi-ethylsuccinyl halide is used as a startingmaterial, the intermediate reaction product is a diamide or a mixedamide-acid halide, that is, a substituted succinamyl halide. Uponheating, these products undergo ring closure to yield the desiredsuccinimide. The foregoing intermediate reaction products are otherexamples of reactive derivatives of :x-rnethyl-e-phenyl-p ethylsuccinicacid suitable for use in the process of the invention. a a

The reaction of zx-methyl-u-phenyl-fi-ethylsuccinic acid or a reactivederivative thereof is carried outwith at least one equivalent andpreferably an excess of methylamine or ammonia. In those cases where anacid halide is employed as the reactive derivative, it is preferable touse at least three equivalents of methylamine or ammonia. If desired,any of a variety of unreactive solvents can be present although in thecase of ot-methyl-a-phenyl-p-ethylsuccinic acid, the process is normallycarried out by first reacting this acid with aqueous ammonia or aqueousmeth- 3,183,245 Patented May 11, 1965 ylamine followed by heating themixture until volatile components including water are removed. Thea-methyl-u-phenyl-fl-ethylsuccinic acid and its reactive derivatives canbe prepared by reacting a lower alkyl ester ofa-cyano-fi-methylcinnamate with potassium cyanide and ethyl bromide toform a lower alkyl ester ofa,fl-dicyano-e-ethyl-/5'-methylphenylpropionate which is then hydrolyzedand decarboxylated by heating with aqueous sulfuric-acetic acid to giveot-methyl-tx-phenyl-B-ethylsuccinic acid. This acid can be converted toreactive derivatives such as the anhydride or the halide by generalprocedures already known.

Also in accordance with the invention,a-methyl-aphenyl-{3-ethylsuccinimide can be produced by heating a cyanocompound of the formula CH CgH5 with a strong base in a solventcontaining water, followed by acidification to convent the resultingsalt form to catnethyl-a-phenyl-[3-ethylsuccinimide and if necessary toconvert the group Y to hydrogen; where Y is hydrogen or a labile groupconvertible to hydrogen and Z is a cyano (-CN) or carbarnoyl (CONHgroup. When Y in the foregoing formula is a labile group convertible tohydrogen, it can represent such groups as lower alkoxycarbonyl(COO-lower alkyl), carba-moyl or carboxyl. In carrying out the processof the invention, these groups readily undergo decarboxylation orhydrolysis followed by decanboxylation. Some examples of suitable strongbases useful in the process of the invention are alkali metal hydroxidesand quaternary ammonium hydroxides. The preferred reagent is an alkalimetal hydroxide such as potassium hydroxide or sodium hydroxide.Although the quantity of the alkali metal hydroxide or other basicreagent can be varied over wide limits, it is preferred to use about 3to 5 moles of the alkali metal hydroxide for each mole of cyanocompound. Some suitable solvents for the reaction are aqueous mixturesof lower alkanols, ethylene glycol, diethylene glycol, dirnethyl ether,or tetrahydrofuran. A preferred solvent mixture is 70-95 of a loweralkanol with 530% water. The temperature at which the process is carriedout is not critical and customarily it is carried out in the range of40200 C. or at the reflux temperature of the solvent. The preferredtemperature range is 60-110 C., and when using ethanol at the refluxtemperature the cyclization is substantially complete within about 4-10hours. The reaction product is present as a salt form in the-basicreaction mixture and is isolated as a-methyl-a-phenyhfi-ethylsuccinimideupon acidification. Where the group Y in the foregoing for-mula is alabile group convertible to hydrogen, it is converted to hydrogen by theacidification operation.

Further in accordance with the invention,N-methyl-amethyl-a-phenylfi-ethylsuccinimide can be produced by reactinga-methyl-a-phenyl-p-ethylsuccinimidc with a methylating agent. Someexamples of suitable methylating agents are esters of methanol such asdimethyl sulfate and methyl halides, and diazomethane. At least oneequivalent and preferably a slight excess of the methylating agent isused. Depending upon the particular methylating agent, a variety ofsolvents and reaction conditions can be used. For example, themethylation with dimethyl J9 reaction is substantially complete Withinan hour or less at 10-40" C.

The compounds of the invention can exist in diastereoisomeric forms. Byfractional crystallization and resolution procedures, the individualdiastereoisomers as well as the optically active components can beobtained if desired. The compounds of the invention have usefulpharmacological properties and are of particular value as tranquilizingagents. Their value as tranquilizing agents is associated with afavorable ratio of anticonvulsant activity to hypnotic activity. Theyhave a comparatively high anticonvulsant activity as determined by theirability to prevent the occurrence of convulsions which normally followthe administration of pentamethylenetetrazole, in conjunction with acomparatively low hypnotic activity. They do not cause the morepronounced central nervous system depression of potent hypnotic agents.An additional advantage of these compounds is that they are eifectiveupon oral administration.

Therapeutic compositions of the compounds of the invention are obtainedby providing a-methyl-a-phenyl-fiethylsuccinimide andN-methyl-u-methyl-u-phenyl-fi-eth ylsuccinimide in dosage unit form inpharmaceutical carriers or diluents. Dosage unit forms for oraladministration are particularly suitable and for this purpose the activeingredient can be incorporated into tablets, powders, capsules,solutions, suspensions and similar forms withpharmaceutically-acceptable solid or liquid carriers or diluents.

The compounds of the invention are employed as tranquilizing agents byadministering a total daily oral dose of about 0.2 to 5.0 g., optionallyin divided portions. The dose is adjusted by first administering acomparatively small quantity and then increasing it as the response isevaluated; the usual total daily oral dose for maintenance is about 0.5to 2.0 g.

The invention is illustrated by the following examples.

Example 1 A mixture of 80 g. of a-methyl-a-phenyl-p-ethylsuccinic acidand 200 ml. of concentrated aqueous ammonia is heated in an open vesseluntil the internal temperatur reaches 210 C. and then maintained at thistemperature for -30 minutes at which time distillation has ceased. Aftercooling the residue is dissolved in ether and the solution is filteredand evaporated. The product, ot-methyl-ot-phenyl-fi-ethylsuccinimide, isdistilled in vacuo; B.P. l90-200 C./5 mm. For further purification thedistillate is dissolved in 50 ml. of methanol and the solution isdiluted with water to the point of cloudiness and allowed to stand. Thewhite solid which separates is collected on a filter and dried. Iffurther purification is desired, g. of this product is dissolved in 70ml. of hot toluene. The solution is chilled and the crystalline productcollected and dried first in air and then in vacuo at 55 C.; M.P. 6566.5C., mixture of diastereoisomers. The individual diastereoisomers areobtained by fractional crystallization from cyclohexane and fromtoluene; M.P. 119-120" C. and 61-63" C.

The starting material can be obtained as follows: 70- g. of potassiumcyanide is added in one portion to 215 g. of ethyla-cyano-[i-methylcinnamate in 500 m1. of absolute ethanol. The mixtureis heated under reflux for one hour, cooled to about 40 C. and thentreated with 130 g. of ethyl bromide added in one portion. The solutionis heated under reflux for six hours, cooled to -30 C. and filtered. Thefiltrate is combined with a 50 ml. washing of hot ethanol, diluted withwater to the point of cloudiness and cooled. The insoluble product,ethyl n p-dicyano-ot-ethyl-fl-methylphenylpropionate, is collected on afilter. This product is added in one portion to a solution of 700 g. ofsulfuric acid, 300 g. of water and 200 g. of glacial acetic acid. Themixture is heated under reflux for twenty hours and cooled. The aqueousphase is removed by decantation and 450 ml. of aqueous sodium hydroxidecontaining 100 g. of sodium hydroxide is added to the residual viscousoil. This mixture is heated under refiux for three hours, cooled,acidified carefully to pH 6, chilled and filtered. The filtrate isacidified to pH 1 and allowed to stand for two days or until theinsoluble product has solidified. This product,ot-mcthyl-a-phenyl-flethylsuccinic acid, is collected on a filter anddried.

Example 2 With continuous stirring 236 g. ofu-methyl-a-phenylfi-ethylsuccinic acid is added to 231 g. of 40% aqueousinethylamine. While stirring is continued, the mixture is graduallyheated to 200 C. The distillate is discarded. The residue consisting ofcrude N-methyl-a-methyl-aphenyl-fl-ethylsuccinimide is fractionated bydistillation in vacuo. The principal fraction is collected at a boilingpoint of about l74180 C./3.03.75 mm. and is the desired product. Iffurther purification is desired, it can be redistilled in vacuo;colorless liquid, B.P. 129 C./ 0.13

The same product is obtained by the substitution of 218 g. ofa-methyl-a-phenyl-p-ethylsuccinic anhydride (prepared by heatingct-methyl-a-phenyl-fi-ethylsuccinic acid with acetyl chloride) for thea-methyl-a-phenyl-fl-ethylsuccinic acid in the foregoing procedure.

Example 3 With stirring, 32.6 g. of ethyla,,B-dicyano-a-etl1yl-flmethylphenylpropionate is added to a solution of33.8 g. of 86% potassium hydroxide in 157 ml. of ethanol and 9.2 ml. ofwater. The mixture is heated under refiux with continued stirring for 8hours and is then filtered to remove precipitated potassium carbonate.The filter cake is washed twice with 20 ml. portions of 95% ethanol andthe combined filtrate and washings are concentrated under reducedpressure below 40 C. to a volume of about 70 ml. This concentratedfiltrate is diluted with an equal volume of cold water and acidified toabout pH 1.0 by the slow addition below 40 C. of 29.9 g. of 37.3%hydrochloric acid. It is then extracted with a total of 50 ml. of ethylacetate in four portions and the combined ethyl acetate extract iswashed three times, each with a solution of 2.5 g. of sodium sulfate in18 ml. of water and then dried over anhydrous magnesium sulfate andfiltered. The filtrate is evaporated under reduced pressure and the oilyresidue of crude a-methyl-a-phenyl-fl-ethylsuccinimide is fractionallydistilled under reduced pressure. The product is obtained as a fractionboiling at l98204 C. at 0.9- 1.4 mm; M.P. 6469 C. followingcrystallization from a mixture of ether, cyclohexane, and petroleumether. This productis a mixture of diastereoisomers. The individualdiastereoisomers are obtained by fractional crystallization fromcyclohexane and from toluene; M.P. 119 120 C. and 61-63 C.

Example 4 A reaction mixture prepared by adding 14.6 g. ofamethyl-a-phenyl-,B-ethylsuccinonitrile to a solution of 11.2 g. of 86%potassium hydroxide in 102 ml. of 95 ethanol and 6 ml. of water isheated under refiux for 6 hours, concentrated under reduced pressure toa volume of about 60 ml., diluted with ml. of cold water and acidifiedto pH 1.0 with hydrochloric acid. The acidified mixture is extractedthree times with 100 ml. portions of ether and the ether extracts arewashed several times with water, dried over anhydrous magnesium sulfateand filtered. The other filtrate is extracted with 100 ml. of 1 N sodiumhydroxide and the aqueous extract is separated and acidified withhydrochloric acid. The insoluble tX-mCthyl-OL- phenyl-p-ethylsuccinimidewhich separates is collected; M.P. 63-66" C., mixture ofdiastereoisomers. The individual diastereoisomers are obtained byfractional crystallization from cyclohexane and from toluene; M.P. 119-120 C. and 61-63 C.

The starting material can be obtained as follows. A

reaction mixture prepared by adding 108 g. of ethyl 04,5-dicyano-u-ethyl-Bmethylphenylpropionate to a solution of 112 g. of 8 6%potassium hydroxide in 553 ml. of 95% ethanol and 32.5 ml. of water isstirred and heated under reflux for 15 minutes. The insoluble potassiumcarbonate is removed by filtration and Washed with 75 ml. of 95%ethanol. The combined filtrate and washing is evaporated under reducedpressure to about one-half its previous volume and then diluted with anequal volume of cold water and acidified to pH 1 with hydrochloric acid,employing external cooling as reqired to maintain the temperature below40 C. The oil which separates upon acidification is extracted with atotal of 600 ml. of ether in three portions and the combined etherextract is washed three times with 125 ml. portions of sodium hydroxidesolution, washed twice with water, dried over anhydrous magnesiumsulfate and filtered. The filtrate is evaporated and the oily residue isfractionally distilled under reduced pressure. Thea-methyl-a-phenyl-B-ethylsuccinonitrile is collected at B1. 130 C. at0.7 mm.

Example 5 A reaction mixture prepared by adding 216 g. ofaethyl-[i-cyano-,8-methyI-Bphenylpropionamide to a solution of 72 g. of86% potassium hydroxide in 660 ml. of 95% ethanol and 39 ml. of water isheated under reflux for 1 hour, evaporated under reduced pressure to avolume of 390 mL, diluted with an equal volume of cold water andacidified to pH 1 with hydrochloric acid. The acidified mixture isextracted three times with 500 ml. portions of ethyl acetate and thecombined ethyl acetate extract is washed several times with water andthen dried over anhydrous magnesium sulfate and filtered. The filtrateis evaporated to yield an oily residue of crudewmethyl-uphenyl-fl-ethylsuccinimide which is then fractionally distilledunder reduced pressure. The product is collected at B1. 198-204 C. at 1mm.; Ml. 64-69 C., mixture of diastereoisomers. The individualdiasteroisomers are obtained by fractional crystallization fromcyclohexane and from toluene; M.P. 1l9120 C. and 61-63 C.

The starting material can be obtained as follows. With stirring, 131 g.of a-methylphenylacetonitrile is slowly added to 39 g. of sodamide in500 ml. of absolute ether. After the addition is complete the mixture isheated under reflux for 2 hours. With continued stirring, 166 g. of 06--bromobutyramide is added in small portions and the mixture is heatedunder reflux for an additional 3 hours and 6 then diluted with 300 ml.of water. The ether phase is separated, washed with water, dried overanhydrous magnesium sulfate and filtered. The filtrate is evaporated toyield a residue of crude a-ethyl-)8-cyano-[3-methyl-[3-phenylpropionamide, suitable for use Without further purification.

Example 6 A solution is prepared by dissolving 21.7 g. ofu-methyla-phenyl-fi-ethylsuccinimide in ml. of water containing 4.8 g.of sodium hydroxide. The solution is cooled and 13.9 g. of dimethylsulfate is added in portions with stirring. Stirring is continued forone more hour and the insoluble oily precipitate ofN-niethyl-a-methyl-tit-phenylp-ethylsuccinimide is extracted with atotal of 300 ml. of ethyl acetate in three portions. The combined ethylacetate extract is washed several times with water, dried over anhydrousmagnesium sulfate and filtered. The filtrate is evaporated under reducedpressure and the oily residue is fractionated by distillation underreduced pressure. The product is collected as a colorless liquid; 13.1.129 C. at 0.13 mm.

We claim:

1. Process for the production of a-methyl-a-phenyl-flethylsuccinirnidewhich comprises heating a cyano compound of the formula References Citedby the Examiner Miller et al.: I. Am. Chem. Society, vol. 73, pages560856-10 1).

NICHOLAS S. RIZZO, Primary Examiner.

1. PROCESS FOR THE PRODUCTION OF A-METHYL-A-PHENYL-BETHYLSUCCINIMIDEWHICH COMPRISES HEATING A CYANO COMPOUND OF THE FORMULA